Distributed X chromosome inactivation in brain circuitry is associated with X-linked disease penetrance of behavior.

The precise anatomical degree of brain X chromosome inactivation (XCI) that is sufficient to alter X-linked disorders in females is unclear. Here, we quantify whole-brain XCI at single-cell resolution to discover a prevalent activation ratio of maternal to paternal X at 60:40 across all divisions of the adult brain. This modest, non-random XCI influences X-linked disease penetrance: maternal transmission of the fragile X mental retardation 1 (Fmr1)-knockout (KO) allele confers 55% of total brain cells with mutant X-active, which is sufficient for behavioral penetrance, while 40% produced from paternal transmission is tolerated. Local XCI mosaicism within affected maternal Fmr1-KO mice further specifies sensorimotor versus social anxiety phenotypes depending on which distinct brain circuitry is most affected, with only a 50%-55% mutant X-active threshold determining penetrance. Thus, our results define a model of X-linked disease penetrance in females whereby distributed XCI among single cells populating brain circuitries can regulate the behavioral penetrance of an X-linked mutation.

Endogenous pathology in tauopathy mice progresses via brain networks.

Neurodegenerative tauopathies are hypothesized to propagate via brain networks. This is uncertain because we have lacked precise network resolution of pathology. We therefore developed whole-brain staining methods with anti-p-tau nanobodies and imaged in 3D PS19 tauopathy mice, which have pan-neuronal expression of full-length human tau containing the P301S mutation. We analyzed patterns of p-tau deposition across established brain networks at multiple ages, testing the relationship between structural connectivity and patterns of progressive pathology. We identified core regions with early tau deposition, and used network propagation modeling to determine the link between tau pathology and connectivity strength. We discovered a bias towards retrograde network-based propagation of tau. This novel approach establishes a fundamental role for brain networks in tau propagation, with implications for human disease.

Synergy in IR-Hybrid CT/C-arm in the setting of critical trauma.

Access to multi-detector computed tomography (MDCT) scanning for interventional procedures can prove to be logistically challenging as resources are often in different areas within the hospital. At some institutions, interventional radiology suites have moved to the operating room, separate from the diagnostic radiology department. At these institutions, complex interventional procedures requiring both fluoroscopy and MDCT may pose logistical challenges, especially as they pertain to timely patient transfers. Hybrid CT/fluoroscopy suite provides rapid, reliable MDCT assessment of trauma patients before and after emergent surgery, as well as access to the entire spectrum of emergent image-guided interventions in the same suite.

Regional, Layer, and Cell-Type-Specific Connectivity of the Mouse Default Mode Network.

The evolutionarily conserved default mode network (DMN) is a distributed set of brain regions coactivated during resting states that is vulnerable to brain disorders. How disease affects the DMN is unknown, but detailed anatomical descriptions could provide clues. Mice offer an opportunity to investigate structural connectivity of the DMN across spatial scales with cell-type resolution. We co-registered maps from functional magnetic resonance imaging and axonal tracing experiments into the 3D Allen mouse brain reference atlas. We find that the mouse DMN consists of preferentially interconnected cortical regions. As a population, DMN layer 2/3 (L2/3) neurons project almost exclusively to other DMN regions, whereas L5 neurons project in and out of the DMN. In the retrosplenial cortex, a core DMN region, we identify two L5 projection types differentiated by in- or out-DMN targets, laminar position, and gene expression. These results provide a multi-scale description of the anatomical correlates of the mouse DMN.

Comparing Occlusive Balloon Performance Using 3-Dimensional Printed Models of Intracranial Aneurysmal Defects.

OBJECTIVE: Balloon remodeling microcatheters are essential in assisting endovascular coiling of brain aneurysms, but the performance and pressure requirements of different balloon types when used in aneurysmal defects are currently unknown. METHODS: We used Tinkercad (Autodesk, Montreal, Quebec) to create model vessels with aneurysmal defects and 3-dimensionally printed these designs with polylactic acid using the Ultimaker2 (Ultimaker, Geldermalsen, Netherlands). We constructed a pressurized box capable of reaching physiologic pressures that housed our vessels and then tested compliant remodeling balloons under fluoroscopy from 3 manufacturers: Hyperglide (Medtronic, Minneapolis, Minnesota, USA), Transform (Stryker Neurovascular, Fremont, California, USA), and Scepter C (Microvention, Tustin, California, USA). Each balloon was inflated to a nominal and supranominal point at each defect, and at each inflation the maximum diameter of the balloon and internal balloon pressure were recorded. The Phillips Intellivue (Phillips, Amsterdam, The Netherlands) monitor was adapted for internal balloon pressure monitoring. A multivariate linear regression analysis was performed to model balloon compliance (balloon diameter divided by pressure). RESULTS: Multivariate regression modeling demonstrated the Scepter balloon had significantly greater compliance compared with both the Hyperglide and Transform balloons (P < 0.001). In addition, we found that Scepter balloons had higher compliance in larger defects compared with the other types of balloons and performance differences based on vessel size. CONCLUSIONS: Scepter balloons require less pressure compared with their counterparts to adequately deform through model defects, specifically in larger aneurysm necks in smaller vessel diameters. This result could inform operators of optimal balloon type and size when trying to minimize balloon pressure in fragile brain aneurysms.

Intermediate to Long-Term Clinical Outcomes of Percutaneous Cryoablation for Renal Masses.

PURPOSE: The purpose of this study was to evaluate the effectiveness and adverse outcomes of percutaneous cryoablation (CA) for treatment of renal masses in a large cohort of patients. MATERIALS AND METHODS: This retrospective analysis included 299 CA procedures (297 masses in 277 patients) performed between July 2007 and May 2018 at a single institution. The mean patient age was 66.1 years (range, 30-93 years) with 65.8% being male. A total of 234 (78.8%) masses were biopsy-proven renal cell carcinoma (RCC). The mean maximal tumor diameter was 2.5 cm (range, 0.7-6.6 cm). Efficacy was assessed only for ablations of biopsy-proven RCC, whereas the evaluation of adverse events and renal function included all masses. Complications were graded according to the Society of International Radiology classification. RESULTS: Major complications occurred in 3.0% of procedures (n = 9), none of which resulted in death or permanent disability. The mean imaging follow-up period was 27.4 months (range, 1-115) for the 199 RCC patients (204 ablated tumors) with follow-up imaging available. Complete response on initial follow-up imaging at mean 4.2 months (range, 0.3-75.6) was achieved in 195 of 204 tumors (95.6%) after a single session and in 200 of 204 tumors (98.0%) after 1 or 2 sessions. Of the RCC patients achieving complete response initially, local recurrence during the follow-up period occurred in 3 of 200 tumors (1.5%). Metastatic progression occurred in 10 of 193 (5.2%) RCC patients without prior metastatic disease during follow-up. CONCLUSIONS: CA for renal masses is safe and remains efficacious through intermediate- and long-term follow-up.

Hierarchical organization of cortical and thalamic connectivity.

The mammalian cortex is a laminar structure containing many areas and cell types that are densely interconnected in complex ways, and for which generalizable principles of organization remain mostly unknown. Here we describe a major expansion of the Allen Mouse Brain Connectivity Atlas resource1, involving around a thousand new tracer experiments in the cortex and its main satellite structure, the thalamus. We used Cre driver lines (mice expressing Cre recombinase) to comprehensively and selectively label brain-wide connections by layer and class of projection neuron. Through observations of axon termination patterns, we have derived a set of generalized anatomical rules to describe corticocortical, thalamocortical and corticothalamic projections. We have built a model to assign connection patterns between areas as either feedforward or feedback, and generated testable predictions of hierarchical positions for individual cortical and thalamic areas and for cortical network modules. Our results show that cell-class-specific connections are organized in a shallow hierarchy within the mouse corticothalamic network.

Outcomes after Peripancreatic Fluid Drainage in Patients with Simultaneous Pancreas-Kidney Transplantation.

PURPOSE: To determine the clinical outcomes of patients who underwent image-guided drainage of peripancreatic fluid collections after simultaneous pancreas-kidney (SPK) transplantation. MATERIALS AND METHODS: A retrospective review of all patients who underwent peripancreatic fluid collection drainage after SPK, from January 2000 to August 2017, at a single institution was performed. Patient characteristics, surgical technique, medication regimen, microbial analysis, and clinical outcomes were reviewed. Thirty-one patients requiring a total of 41 drainages were included in this study. The median age was 44 years (range 30-58 years), and median time between SPK and drainage was 28 days (range 8 to 3,401 days). Fisher's exact test, unpaired Student t-tests, and Pearson correlations were used for statistical analysis. RESULTS: Fever (51%) and abdominal pain (31%) were the most common presenting symptoms. The average amount of fluid drained at the time of drain placement was 97 mL (SD 240 mL). The average time spent with a drain in place was 33 days (SD 31 days). Microorganisms were isolated in the fluid of 22 of 41 drainages (54%), with mixed gastrointestinal flora being the most common. No further intervention was needed in 34 of 41 drainages (82%). However, drainage failed in 5 of 31 patients (16%), requiring surgical intervention with removal of the pancreas transplant. CONCLUSIONS: Percutaneous drainage of peripancreatic fluid collections after SPK transplantation is a safe and effective treatment option.

High-resolution data-driven model of the mouse connectome.

Knowledge of mesoscopic brain connectivity is important for understanding inter- and intraregion information processing. Models of structural connectivity are typically constructed and analyzed with the assumption that regions are homogeneous. We instead use the Allen Mouse Brain Connectivity Atlas to construct a model of whole-brain connectivity at the scale of 100 µm voxels. The data consist of 428 anterograde tracing experiments in wild type C57BL/6J mice, mapping fluorescently labeled neuronal projections brain-wide. Inferring spatial connectivity with this dataset is underdetermined, since the approximately 2 × 105 source voxels outnumber the number of experiments. To address this issue, we assume that connection patterns and strengths vary smoothly across major brain divisions. We model the connectivity at each voxel as a radial basis kernel-weighted average of the projection patterns of nearby injections. The voxel model outperforms a previous regional model in predicting held-out experiments and compared with a human-curated dataset. This voxel-scale model of the mouse connectome permits researchers to extend their previous analyses of structural connectivity to much higher levels of resolution, and it allows for comparison with functional imaging and other datasets.

An Abnormal Tibial Position Is Associated With Alterations in the Meniscal Matrix: A 3-Year Longitudinal Study After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: An altered tibial position is still present despite anterior cruciate ligament (ACL) reconstruction. It has been demonstrated that an abnormal tibial position after an ACL injury may play a role in subsequent injuries to the meniscus, which can lead to early cartilage degeneration. PURPOSE: To determine changes in both the tibial position and the meniscal matrix present before and after ACL reconstruction as well as to evaluate the association between these 2 variables in ACL-injured knees 3 years after reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Bilateral knee magnetic resonance imaging (MRI) of 32 patients with unilateral ACL injuries was performed before reconstruction; 13 control participants also underwent MRI. Follow-up MRI was performed up to 3 years after surgery. Tibial position, internal tibial rotation, and T1ρ and T2 values of the menisci were calculated using an in-house MATLAB program. Student t tests and multiple linear regression were used to compare differences between injured, uninjured, and control knees as well as to assess correlations between the tibial position at 3 years and 3-year changes in quantitative MRI meniscal relaxation values. RESULTS: The tibial position of injured knees was more anterior than that of uninjured knees at baseline, 6 months, and 1, 2, and 3 years (P < .05 for all). The T1ρ and T2 values of the menisci of injured knees were greater than those of uninjured and control knees in the posterior lateral and posterior medial horns up to 1 and 2 years after surgery, respectively (P < .05 for all). The tibial position at 3 years was associated with increased T2 values from baseline to 3 years in the posterior medial horn (ß = 0.397; P = .031) and anterior medial horn (ß = 0.360; P = .040). CONCLUSION: Results of the current study indicate that there is a persistently altered tibial position after ACL reconstruction. Initial preoperative meniscal abnormalities show prolonged but gradual improvement. Additionally, correlations between the tibial position and changes in the medial meniscal matrix suggest that the tibial position may play a role in the increased susceptibility to medial meniscal tears seen after reconstruction. The development of newer surgical techniques must address a persistently altered tibial position. Quantitative MRI is an effective instrument to evaluate meniscal matrix changes and can serve as an early radiological tool for meniscal injuries.

Whole brain imaging reveals distinct spatial patterns of amyloid beta deposition in three mouse models of Alzheimer's disease.

A variety of Alzheimer's disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid ß (Aß) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Aß deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of Aß plaques across age in three APP-overexpression mouse lines (APP/PS1, Tg2576, and hAPP-J20) using in vivo labeling with methoxy-X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two-photon tomography and labeled plaques were detected using custom-built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain-wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP-J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; for example, the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP-J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional Aß deposition patterns described in AD.

Phosphorylation of tau at Y18, but not tau-fyn binding, is required for tau to modulate NMDA receptor-dependent excitotoxicity in primary neuronal culture.

BACKGROUND: Hyperexcitability of neuronal networks can lead to excessive release of the excitatory neurotransmitter glutamate, which in turn can cause neuronal damage by overactivating NMDA-type glutamate receptors and related signaling pathways. This process (excitotoxicity) has been implicated in the pathogenesis of many neurological conditions, ranging from childhood epilepsies to stroke and neurodegenerative disorders such as Alzheimer's disease (AD). Reducing neuronal levels of the microtubule-associated protein tau counteracts network hyperexcitability of diverse causes, but whether this strategy can also diminish downstream excitotoxicity is less clear. METHODS: We established a cell-based assay to quantify excitotoxicity in primary cultures of mouse hippocampal neurons and investigated the role of tau in exicitotoxicity by modulating neuronal tau expression through genetic ablation or transduction with lentiviral vectors expressing anti-tau shRNA or constructs encoding wildtype versus mutant mouse tau. RESULTS: We demonstrate that shRNA-mediated knockdown of tau reduces glutamate-induced, NMDA receptor-dependent Ca2+ influx and neurotoxicity in neurons from wildtype mice. Conversely, expression of wildtype mouse tau enhances Ca2+ influx and excitotoxicity in tau-deficient (Mapt -/-) neurons. Reconstituting tau expression in Mapt -/- neurons with mutant forms of tau reveals that the tau-related enhancement of Ca2+ influx and excitotoxicity depend on the phosphorylation of tau at tyrosine 18 (pY18), which is mediated by the tyrosine kinase Fyn. These effects are most evident at pathologically elevated concentrations of glutamate, do not involve GluN2B-containing NMDA receptors, and do not require binding of Fyn to tau's major interacting PxxP motif or of tau to microtubules. CONCLUSIONS: Although tau has been implicated in diverse neurological diseases, its most pathogenic forms remain to be defined. Our study suggests that reducing the formation or level of pY18-tau can counteract excitotoxicity by diminishing NMDA receptor-dependent Ca2+ influx.

Increasing the Receptor Tyrosine Kinase EphB2 Prevents Amyloid-ß-induced Depletion of Cell Surface Glutamate Receptors by a Mechanism That Requires the PDZ-binding Motif of EphB2 and Neuronal Activity.

Diverse lines of evidence suggest that amyloid-ß (Aß) peptides causally contribute to the pathogenesis of Alzheimer disease (AD), the most frequent neurodegenerative disorder. However, the mechanisms by which Aß impairs neuronal functions remain to be fully elucidated. Previous studies showed that soluble Aß oligomers interfere with synaptic functions by depleting NMDA-type glutamate receptors (NMDARs) from the neuronal surface and that overexpression of the receptor tyrosine kinase EphB2 can counteract this process. Through pharmacological treatments and biochemical analyses of primary neuronal cultures expressing wild-type or mutant forms of EphB2, we demonstrate that this protective effect of EphB2 depends on its PDZ-binding motif and the presence of neuronal activity but not on its kinase activity. We further present evidence that the protective effect of EphB2 may be mediated by the AMPA-type glutamate receptor subunit GluA2, which can become associated with the PDZ-binding motif of EphB2 through PDZ domain-containing proteins and can promote the retention of NMDARs in the membrane. In addition, we show that the Aß-induced depletion of surface NMDARs does not depend on several factors that have been implicated in the pathogenesis of Aß-induced neuronal dysfunction, including aberrant neuronal activity, tau, prion protein (PrP(C)), and EphB2 itself. Thus, although EphB2 does not appear to be directly involved in the Aß-induced depletion of NMDARs, increasing its expression may counteract this pathogenic process through a neuronal activity- and PDZ-dependent regulation of AMPA-type glutamate receptors.

DNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice.

Maintaining DNA integrity is vital for all cells and organisms. Defective DNA repair may contribute to neurological disorders, including Alzheimer's disease (AD). We found reduced levels of BRCA1, but not of other DNA repair factors, in the brains of AD patients and human amyloid precursor protein (hAPP) transgenic mice. Amyloid-ß oligomers reduced BRCA1 levels in primary neuronal cultures. In wild-type mice, knocking down neuronal BRCA1 in the dentate gyrus caused increased DNA double-strand breaks, neuronal shrinkage, synaptic plasticity impairments, and learning and memory deficits, but not apoptosis. Low levels of hAPP/Amyloid-ß overexpression exacerbated these effects. Physiological neuronal activation increased BRCA1 levels, whereas stimulating predominantly extrasynaptic N-methyl-D-aspartate receptors promoted the proteasomal degradation of BRCA1. We conclude that BRCA1 is regulated by neuronal activity, protects the neuronal genome, and critically supports neuronal integrity and cognitive functions. Pathological accumulation of Aß depletes neuronal BRCA1, which may contribute to cognitive deficits in AD.

Tau reduction prevents Aß-induced axonal transport deficits by blocking activation of GSK3ß.

Axonal transport deficits in Alzheimer's disease (AD) are attributed to amyloid ß (Aß) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant Aß oligomers. Relevance of these findings to naturally secreted Aß and mechanisms underlying tau's enabling effect are unknown. Here we demonstrate deficits in anterograde axonal transport of mitochondria in primary neurons from transgenic mice expressing familial AD-linked forms of human amyloid precursor protein. We show that these deficits depend on Aß1-42 production and are prevented by tau reduction. The copathogenic effect of tau did not depend on its microtubule binding, interactions with Fyn, or potential role in neuronal development. Inhibition of neuronal activity, N-methyl-d-aspartate receptor function, or glycogen synthase kinase 3ß (GSK3ß) activity or expression also abolished Aß-induced transport deficits. Tau ablation prevented Aß-induced GSK3ß activation. Thus, tau allows Aß oligomers to inhibit axonal transport through activation of GSK3ß, possibly by facilitating aberrant neuronal activity.